Coronary thrombosis on a ruptured coronary plaque is the main pathophysiologic event that leads to acute coronary syndromes (ACS). Clinical methods currently utilized to treat this are fibrinolytic agents or percutaneous coronary interventions, combined with anti-platelet agents. Several in vitro and pre-clinical investigations have examined the effect of ultrasound to enhance thrombolysis (termed sonolysis). Transcutaneous high mechanical index (MI) ultrasound and intravenous microbubbles have successfully recanalized peripheral vessel thromboses in animal studies. Our preliminary mechanistic studies have shown that an essential component for effective sonolysis is applying high MI cavitation-inducing impulses only when low MI imaging detects microbubbles as they transit through small micro-channels within the thrombus. The potential for transthoracic sonolysis in ACS is limited by several factors, including attenuation of the ultrasound beam, coronary size and motion relative to the ultrasound field, downstream microvascular flow, and safety factors related to the high MI impulses. The central hypothesis of this study is that coronary recanalization in ACS with sonolysis can be over 90% successful when using three-dimensional high MI impulses guided by low MI pulse sequence schemes which detect microbubbles within the affected coronary artery perfusion bed. In this project we will test the effect of attenuation, insonation angle, and peak negative acoustic pressure on the success rate of thrombus issolution with high MI guided ultrasound. Coronary simulation studies will be performed which examine the effect of these variables, as well as what effect three-dimensional diagnostic ultrasound and microbubble targeting strategies have on increasing the amount of cavitation at the site of a thrombosed vessel during the guided high MI impulses. These findings will then be extended to an open-chest atherosclerotic pig model, where we will examine what effect two- versus three-dimensional high MI impulses have on cavitation within the thrombosed coronary artery and downstream microvasculature, and how this impacts coronary recanalization rates. Finally, we will apply these findings to a closed-chest atherosclerotic pig model. We will prospectively compare the effectiveness of the guided ultrasound approach to conventional fibrinolytic therapy in both a) recantalizing the thrombosed coronary artery and b) improving microcirculatory flow. With the completion of these studies, a Phase I clinical trials could potentially be initiated exploring whether three-dimensional sonolysis could be utilized in the emergency department or pre-hospital setting to treat patients with acute coronary syndromes. Public Health Relevance Statement (provided by applicant): The three-dimensional/microbubble sonolysis could be utilized in the emergency department or pre-hospital setting to treat patients with acute coronary syndromes. It would serve as a more rapid, less costly, and safer approach to acute coronary syndromes than fibrinolytic therapy or emergent percutaneous coronary interventions.